March 1, 2013

A study led by researchers at Boston University School of Medicine (BUSM) has identified epigenetic mechanisms that connect a variety of diseases associated with inflammation. Utilizing molecular analyses of gene expression in macrophages, which are cells largely responsible for inflammation, researchers have shown that inhibiting a defined group of proteins could help decrease the inflammatory response associated with diseases such as obesity, type 2 diabetes, cancer and sepsis.

The study, which is published online in the Journal of Immunology, was led by first author Anna C. Belkina, MD, PhD, a researcher in the department of microbiology at BUSM, and senior author Gerald V. Denis, PhD, associate professor of pharmacology and medicine at BUSM.

Epigenetics is an emerging field of study exploring how genetically identical cells express their genes differently, resulting in different phenotypes, due to mechanisms other than DNA sequence changes.

Previous studies have shown that a gene, called Brd2, is associated with high insulin production and excessive adipose (fat) tissue expansion that drives obesity when Brd2 levels are low and cancer when Brd2 levels are high. The Brd2 gene is a member of the Bromodomain Extra Terminal (BET) family of proteins and is closely related to Brd4, which is important in highly lethal carcinomas in young people, as well as in the replication of Human Immunodeficiency Virus (HIV).

The BET family proteins control gene expression epigenetically by acting on chromatin, the packaging material for genes, rather than on DNA directly. This mechanism of action is being explored because the interactions are not reflected in genome sequencing information or captured through DNA-based genetic analysis. In addition, this layer of gene regulation has recently been shown to be a potential target in the development of novel epigenetic drugs that could target several diseases at once.

The study results show that proteins in the BET family have a strong influence on the production of pro-inflammatory cytokines in macrophages. This indicates that the defined family of proteins govern many aspects of acute inflammatory diseases, such as type 2 diabetes, sepsis and cardiovascular disease, among others, and that they should be explored as a potential target to treat a wide variety of diseases.

"Our study suggests that it is not a coincidence that patients with diabetes experience higher risk of death from cancer, or that patients with chronic inflammatory diseases, such as atherosclerosis and insulin resistance, also are more likely to be obese or suffer from inflammatory complications," said Belkina. "This requires us to think of diverse diseases of different organs as much more closely related than our current division of medical specialities allows."

Future research should explore how to successfully and safely target and inhibit these proteins in order to stop the inflammatory response associated with a variety of diseases.

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